Process of preparing pteroic acid and amino acid amides thereof



Patented June 7, 1949 UNITED srmas PATENT OFFICE :lames H. Boothe, PearlRiver, N. Y., assignor to American CyanamidiComptmy, New York, N. Y., acorporation of Maine No Drawing. ApplicationMay 3, 1947, Serial No.745,719

7 Claims. (Cl. 260- 251 1 2 The present invention relates to a newmethod in the form of one of its acid salts, such as the of preparingorganic acids. More particularly, it sulfate or hydrochloride.

relates to a method of preparing pteroic acid and As the secondintermediate, any N(acy'l) -'N- amino acid amides thereof.(beta-'d'ihalo-gamma haloprcpyl) para-amino- Pt'er'oic acid is the nameused to describe the 5 benzo'ic acidc'an beused. It is preferred thatthe compound having the following somewhat unhalogens be allalike.However, they can be-difwieldy chemical name,4([(2-amino-4-hydroxyferen't. An important group lof intermediates "I6-pyrimido -[4,5-blpyrazyl)methyl]amino) bencan use are the amino acidamides of N (acyl) -N- zoic acid. (beta-dihalo-gamma halopropyl)para-amino- An important amino acid amide of pteroic acid 10 benzoicacids, such as, the amides formed by reis that formed by glutamic acidand pteroic acid acting an N'(acyl) -N-'(beta-dihalo-gamma halocommonlycalled pteroylglutamic acid. This propyl) paraaminob'enzoic acid withglutamic compound and methods of synthesizing it have acid, asparticacid, glycine, alanine, leucine, inbeen described by the presentinventor and cosovaline, cysteine and the like. The amino acids workersin Science, vol. 103, May 31, 1946, pages may be natural or syntheticand may be in any 667-669. As also noted there, pteroic acid is acof thed, l or-dl forms. Theseamimo acid amides tive for Streptococcus faecalisR and pteroylpossess free carboxyl groups, and, as will be apglutamicacid is active for Streptococcus fa'ecalis parent, the salts and estersthereof may likewise R as well as L. gasei and is useful in the treatbeemployed. men-t'of certain diseases of the circulatory system, Thereaction of the present invention can be The new process of the presentinvention'incarried out at temperatures of from about 20 wolves severe]reactions which can be illustrated toabout 120 C. although I prefer atemperature as follows: of from 70 to about .110 C.

r RI locale-Cs ix x I aliphatic 1 halogen 1320- =CH2 O acid -------sauhydride e 0R *0 0 & OR

OH N-GHT I N GHENHOG-OR sHX ROH CIOR in which R is an acyl radical, Xrepresents one The reaction is usually complete in a matter of thehalogens such as chlorine or bromine, and of half an hour to an hour,although it may ex- R represents an OH group or an amide forming tendover a period of 15 minutes to 2 or 3 hours.

radical, such as -NHR" which represents the It is preferable to carryout the reaction in a residue of an amino acid. The various steps 4mildly alkaline solution such as an aqueous solushown above aredescribed in detail in the extion of an alkali metal hydroxide. Othersol-- ample. vents can be used such as ethanol, methanol, d1-

The compound 2,4,5-triamino pyrimidone-fi is oxane and the like whichare made mildly alkaknown. It may exist in whole, or in part, in oneline by the addition of compounds such as sodium or more tautomeric orresonant forms, such as, acetate, sodium carbonate and the like.

for example, 2,4,5-triamino-6-hydroxypyrimidine. The invention isillustrated in greater particu- As would be expected, these tautomericforms rel arity in the following example, in which pteroic act similarlyand reference hereinafter to the one acid is prepared. It will beunderstood, of course, tautomer includes the like use of any of thevarithat this example is merely illustrative of the ous tautomers. Thecompound can also be used process and that other important compounds canbe prepared by process, such as, pteroylglutamic acid.

A mixture of 34.9 g. sodium carbonate, 90.2 g. p-aminobenzoic acid, and131.7 g. 2,3-dibrompropene is refluxed fifteen hours in 1300 cc. ofethanol. The reaction mixture is concentrated under reduced pressure toabout 500 cc. and then poured into 3 liters of cold water containing 50cc. of concentrated HCl. The solution is cooled two hours in an icebath, filtered, and the precipitate Washed with water. The precipitateis dried over calcium chloride and crystallized from about 2.3 liters ofchloroform using activated charcoal to clarify the solution. A yield of85.0 g. of N-(beta-bromallyl) para-amino benzoic acid is obtained.

To 20 g. of N-(beta-bromallyl)para-aminobenzoic acid is added 100 cc.acetic anhydride and the mixture refluxed thirty minutes. While thesolution is still hot, 18 cc. of water is added in small portions withshaking. The solution is then cooled, filtered, and poured into 1 literof cold water. The product is filtered off after cooling several hoursand dried. On crystallizing from a benzene-chloroform mixture it comesdown in large, White crystals. A yield of 21 g. of N- (acetyl) N(betabromallyl) para-aminobenzoic acid having a melting point of 153.5 to154.5" C. is obtained.

To 5 g. of N(acety1)-N-(beta-bromal1yl)paraaminobenzoic acid dissolvedin 40 ml. dry chloroform is slowly added 2.68 g. bromine previouslydissolved in 20 cc. of chloroform. After about 5 cc. of bromine solutionis added, an oily precipitate begins to form which soon turns to rathersticky yellow crystals. After all the bromine is added, the solution iscooled and filtered. The yellow crystalline precipitate is washed withchloroform and dried in a vacuum desiccator. The product obtained isN(acetyl) -N- (beta-dibromogamma-bromopropyl) para-aminobenzoic acid.

To 141 of 2,4,5-triaminopyrimidone-6 dissolved in 10 cc. 0.5 N-sodiumhydroxide containing a trace of sodium hydrosulfite is added 458 mg. ofN(acetyl) -N(beta-dibromo-gamma-bromopropyDpara-aminobenzoic acid andthe solution is heated 1 hour on the steam bath. It is then cooled andneutralized to pH 3-4 with HCl. The yellowish-brown ppt. is centrifugedand washed with water. It is redissolved in dilute alkali and treatedwith activated carbon. It is then precipitated with acid, washed anddried. The prod uct contained pteroic acid and was active against S.fecalis R.

I claim:

1. A method which comprises reacting together2,4,5-triamino-6-hydroxy-pyrimidine and a member of the group consistingof N(acyl)-N(betadihalo gamma halopropyl) para aminobenzoic 4 acids andamino acid amides thereof, whereby compounds having the general formula,

I N tK TCHrNHQoOR NH2-L\N N/ the general formula,

N TomNHQcoon NHPL is produced and recovered.

3. A method which comprises reacting together2,4,5-triamino-6-hydr0xy-pyrimidine and N(acetyl)-N(oeta-diha1o gammahalopropyDparaaminobenzoic acid whereby a compound having the generalformula,

is produced and recovered.

4. A method which comprises reacting together2,4,5-triamino-6-hydroxy-pyrimidine and N(acetyl) N(beta dibromo gammabromopropyl) para-aminobenzoic acid, whereby pteroic acid is producedand recovered.

5. A method which comprises reacting together2,4,5-triamino-6-hydroxy-pyrimidine and N(acetyl) N(beta dichloro gammachloropropyl) para aminobenzoic acid whereby pteroic acid is producedand recovered.

6. A method which comprises reacting together2,4,5-triamino-6-hydroXy-pyrimidine and N(ace-. tyl) -N(beta-bromo,beta, gamma-dichloropropyl) para-aminobenzoic acid whereby pteroic acidis produced and recovered.

7. A method which comprises reacting together2,4,5-triamino-6-hydroxypyrimidine and N(acetyl) -N(beta-chloro, beta,gamma-dibromopropyl) para-aminobenzoyl glutamic acid wherebypteroylglutamic acid is produced and recovered.

JAMES H. BOOTHE.

No references cited.

